The present invention relates to thermally-stable dosage forms of S-2-(3-aminopropylamino)ethyl dihydrogen phosphorothioate (amifostine), and to methods of making same. The reconstituted dosage forms of the invention are suitable for administration to humans, for example, as a radio- or chemoprotectant agent.
The compound S-2-(3-aminopropylamino)ethyl dihydrogen phosphorothioate (which is also known as amifostine, ethiofos, Ethyol(copyright), NSC 296961, and WR-2721 and which will hereinafter be referred to as xe2x80x9camifostinexe2x80x9d) and other aminothiol compounds are disclosed in U.S. Pat. No. 3,892,824. These compounds were originally developed as antiradiation agents (radio-protectants), in particular to be used prior to exposure to x-ray or nuclear radiation, to protect against the harmful effects of such exposure which may be encountered during military conflicts.
In addition to its utility as a military antiradiation agent, amifostine has demonstrated excellent utility as a non-military radioprotectant and chemoprotectant, i.e., as a protectant administered prior to therapy to reduce the undesirable adverse effects which arise during the use of chemotherapy and radiation therapy in the treatment of cancer. Nygaard et al., eds, Radioprotectors and Anticarcinogens, Academic Press, Inc., New York, pp. 73-85 (1983); Grdina et al., Carcinogenesis (London) 6:929-931 (1985). In addition, these compounds have been reported to afford protection against the adverse effects of chemotherapeutic agents, for example, alkylating agents such as cisplatin, when administered before or concurrently with the chemotherapeutic agent. Jordan et al., Exp. Mol. Pathol. 36:297 (1982); Doz et al., Cancer Chemother. Pharmacol. 28:308 (1991). Similarly, it has been reported that amifostine has been used experimentally prior to therapy to protect HIV-infected patients (AIDS) from the harmful side effects of 3xe2x80x2-azido-3xe2x80x2-deoxythymidine (AZT) therapy. International Published Application WO 90/14007, published Nov. 29, 1990. Amifostine and its derivatives have been shown to exert these reported protective effects without affecting the beneficial properties of the administered therapeutic agents. This is, in the case of chemotherapy, believed to be due to the selective uptake of the protective thiol and other metabolites into normal tissue. Yuhas, Cancer Res. 40:1519-1524 (1980); Yuhas, Cancer Treat. Rep. 63:971-976 (1979).
Amifostine and related aminothiol compounds have also been shown to stimulate bone marrow growth. See, e.g., International Published Application WO 96/25045 published Aug. 22, 1996; and List et al., Proc. Am. Soc. Clin. Oncol. 15:449 [1403] [Abstract]. Currently, amifostine is in Phase II clinical trials as a bone marrow stimulant in patients suffering from myelodysplastic syndrome. Pre-exposure with aminothiol compounds is capable of causing the bone marrow function to more rapidly recover following chemotherapy. List et al., Semin. Oncol. 23 (4) Supp. 8:58-63 (1996).
Presently, amifostine is indicated to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian or non-small cell lung cancer. Physicians"" Desk Reference 52nd ed., p. 500-502 (1998).
Amifostine is considered a prodrug. Amifostine is metabolized to the cytoprotective free thiol by dephosphorylation catalyzed by alkaline phosphatase. See, e.g., Ryan, S. V., et al., J. Clin. Pharm. 36(4):365-373 (1996). Amifostine exerts protective effects without significantly affecting the beneficial properties of the administered therapeutic agents largely because of the selective uptake of the thiol into normal tissue.
In its most common use, amifostine is administered parenterally, including by bolus injection and intravenous infusion. Amifostine is also being developed for subcutaneous administration. Since these routes circumvent the protective barriers of the human body, exceptional purity of the dosage form must be achieved. Because the dosage form must be free of microoganisms and insoluble particulates, the process used in preparing it must embody Good Manufacturing Practices (xe2x80x9cGMPxe2x80x9d) that will produce and maintain the required quality of the product in terms of sterility and therapeutic effectiveness. Sterility is especially important in the treatment of cancer and AIDS patients, because in many instances they are already immuno-compromised and therefor highly susceptible to infections.
The amifostine bulk drug (which is distinct from the dosage form) can exist as a bulk crystalline trihydrate which is believed to be relatively temperature stable. Such a crystalline form is described by Karle et al., Acta Cryst. C44:135-138 (1988). The bulk drug, however, is not sterile, and so cannot be reconstituted into a pharmaceutical product suitable for parenteral administration to humans.
Several methods of sterilizing bulk drugs are described in Remington""s Pharmaceutical Sciences, 18th ed. (1990). These include, for example, steam sterilization, wherein a drug is exposed to high pressure steam at a minimum temperature of 121xc2x0 C. This and other methods that require heating, however, cannot effectively be used to sterilize bulk crystalline amifostine. This is because crystalline amifostine loses water at about 70xc2x0 C. to about 75xc2x0 C. The loss of water facilitates degradation by a hydrolysis reaction that forms phosphoric acid and 2-[(3-aminopropyl)amino]ethane thiol. See, e.g, Risley, J. M. and Van Etten, R. L., Biochem. Pharmacol. 35:1453-1458 (1986). Amifostine has thus been sterilized by dissolving it in an aqueous solution which is then sterilized by membrane filtration. Substantial practical problems related to the packaging of bulk, solid amifostine using the so-called xe2x80x9cdry fillingxe2x80x9d or xe2x80x9cpowder fillingxe2x80x9d method were thus avoided. These problems include producing sterile amifostine bulk, the difficulty in the manual manipulation of powders, the need to mill the powders to acceptable particle size and flowability, difficulty in maintaining particle-free, aseptic conditions, and the difficulty in supplying the precise dosages into individual vials.
In solution, however, amifostine is again susceptible to degradation by hydrolysis. For this reason, a prior process has sterilized an amifostine solution by filtration, and then lyophilized (freeze-dried) the amifostine solution under the following conditions: about 5 ml of a solution of 100 mg/ml amifostine and 100 mg/ml mannitol placed in vial was loaded into a freeze-drier at 0xc2x0 C. and then solidified at xe2x88x9245xc2x0 C. The vials were kept at xe2x88x9245xc2x0 C. for 2 hours, after which time the freeze drying chamber was evacuated to 100 xcexcm Hg. The self temperature was then raised to 0xc2x0 C. over 12 hours and then maintained at 0xc2x0 C. for 2 hours. The shelf temperature was finally raised to 25xc2x0 C., at which temperature the vials were kept for 24 hours. This method produced a sterile amorphous form of amifostine suitable for parenteral administration to a patient (which is hereinafter referred to as xe2x80x9cAmorphous Amifostine Ixe2x80x9d). Physicians"" Desk Reference, 51st ed. (1997) p. 485-486. This method also allowed easy production of vials containing predetermined amounts of sterile, lyophilized amifostine.
Unfortunately, Amorphous Amifostine I was thermally unstable and hydrolyzed over time at temperatures above 0xc2x0 C. For example, a typical sample of Amorphous Amifostine I kept at 25xc2x0 C. for about one month formed about 6 to 7 weight percent of the degradation product 2-[(3-aminopropyl)amino]ethane thiol. This was the state of the art when the amorphous form of amifostine was approved by regulatory authorities as having a shelf life of 24 months when stored at temperatures of between about 2xc2x0 C. and 8xc2x0 C. See, e.g., Ethyol(copyright) European Summary of Product Characteristics (1997) (xe2x80x9cEthyol(copyright) SmPCxe2x80x9d). In fact, the Amorphous Amifostine I dosage form was generally packaged, shipped, and stored at temperatures below about 8xc2x0 C. Further, in the United States, the amorphous form of amifostine was approved by the Food and Drug Administration as having a shelf life of 15 months when stored at temperatures of between about 2xc2x0 C. and 8xc2x0 C.
Temperature instability imposes upon manufacturers and users packaging, storage and shipping requirements that increase the cost of handling the drug and make its use by hospitals and clinics more difficult, and may even prevent its use in developing countries which often lack temperature controlled storage maintenance capabilities.
In recognition of the need for a dosage form of amifostine that is more thermally-stable than Amorphous Amifostine I, research has been directed at finding new stable and sterile dosage forms of amifostine. For example, Jahansouz and coworkers studied the stability of amifostine and suggested that temperature instability of Amorphous Amifostine I is related to its degree of water content. Jahansouz, H., et al. Pharm. Res. 7(9):S195 (1990) [Abstract].
Recently, instead of attempting to increase the stability of dosage forms of amorphous amifostine such as Amorphous Amifostine I, researchers focused on creating stable and sterile crystalline dosage forms. For example, it was reported that amifostine xe2x80x9cundergoes solid state transitions from the amorphous to crystalline phases by treatment of the freeze-dried products with varying humidity.xe2x80x9d Further, the stability of rehydrated forms of amifostine was allegedly increased by the addition of certain excipients. Zadeii, J. M., et al., Pharm. Res. 8(10):S172 (1991) [Abstract]. This abstract does not, however, describe the rehydration process in any detail, nor does it describe the degree of stabilization provided by the two excipients it discloses. In addition, the abstract provides no detail as to how and when particular excipients should be combined with amifostine to yield the alleged more stable rehydrated forms (i.e., whether the excipients were combined with amifostine prior to, during, or after its rehydration), or whether the process should differ for different excipients. Finally, a novel dosage form of sterile, thermally-stable crystalline amifostine was discovered. U.S. Pat. Nos. 5,424,471 and 5,591,731.
Presently, that sterile crystalline dosage form of amifostine is sold under the trade name Ethyol(copyright). Physicians"" Desk Reference, 52nd ed. (1998) p. 500-502. A crystal structure and preparation of a dosage form, which exhibits greater thermal stability than Amorphous Amifostine I, is described by U.S. Pat. Nos. 5,424,471 and 5,591,731. Generally, this thermally-stable crystalline dosage form is made by dissolving bulk amifostine in a solvent solution (that allows precipitation of amifostine upon cooling below 0xc2x0 C.), followed by sterilization, precipitation and lyophilization of the compound. Because the crystallinity, and hence the stability, of this amifostine dosage form requires three water molecules per molecule, the lyophilization used to provide the final product must be carefully controlled to ensure the required degree of hydration. Once made, the stable crystalline dosage form may be stored at room temperature with minimal degradation: it exhibits less than 2 weight percent degradation when kept at 40xc2x0 C. for 14 days. U.S. Pat. No. 5,591,731.
Although newly developed sterile crystalline dosage forms of amifostine reduce or eliminate many of the problems associated with Amorphous Amifostine I, production of such can be costly, difficult and/or dangerous. For example, the production of crystalline Ethyol(copyright) requires the use of explosive solvents which must be handled with care and strictly isolated from oxygen. Such solvents also contain impurities not typically found in water that must be removed to ensure that the dosage form is suitable for reconstitution and administration to a patient. For example, ethanol often contains acetone, methanol, H2SO4, MnO4, and other toxic residues. See, eg., Aldrich Catalog (1998-1999), pages 746-747. The production of crystalline amifostine dosage forms further requires long lyophilization drying times in order to ensure precise amifostine hydration.
In view of the above-described and other difficulties associated with the production of sterile crystalline dosage forms of amifostine, there remains a need for a stable, sterile amorphous dosage form, as well as an efficient and inexpensive means of its production.
The invention also encompasses non-sterile and/or bulk thermally-stable amorphous amifostine. To applicants"" knowledge, to date an amorphous thernally-stable amifostine has not been previously disclosed. In preferred embodiments, the invention encompasses thermally-stable dosage forms of amifostine.
The present invention encompasses non-sterile and/or bulk thermally-stable amorphous amifostine. To applicants"" knowledge, amorphous thermally-stable amifostine has not been previously disclosed. In preferred embodiments, the invention encompasses thermally-stable dosage forms of amifostine.
The invention encompasses the following thermally-stable and sterile dosage forms: a dosage form which comprises amorphous amifostine; an amorphous dosage form which comprises amifostine; and a dosage form that is suitable for reconstitution with a pharmaceutically acceptable vehicle into an injectable particulate-free drug product suitable for parenteral administration to a subject, which comprises amorphous amifostine.
The invention also encompasses a room temperature stable dosage form comprising sterile amorphous amifostine.
The invention also includes a room temperature stable amorphous dosage form comprising sterile, amorphous amifostine.
This invention is further directed to a refrigerated stable dosage form comprising sterile amorphous amifostine.
The dosage forms of this invention may comprise a stabilizer. It is preferred that the molar ratio of stabilizer to amifostine be between about 0.05 and about 5.0, more preferably between about 0.1 and about 1.0, and most preferably between about 0.2 and about 0.5. Preferred stabilizers are compounds having amide or amino acid moieties. A most preferred stabilizer is nicotinamide.
The dosage form of the present invention may also comprise an excipient. Suitable excipients include sodium chloride, citric acid, tartaric acid, gelatin and carbohydrates such as dextrose, sucrose, sorbitol, inositol, dextran, and mannitol, ethylenediamine-tetraacetic acid (EDTA), sodium deoxycholate, sodium taurocholate and dietylenetriamine-pentaacetic acid (DTPA). Finally, the dosage forms may also contain up to about 20 percent water without significant loss of thermal stability.
The present invention is further directed to a process of making a thermally-stable and sterile amorphous dosage form of amifostine, and to the products of that process.
As used herein, the terms xe2x80x9cbulk amifostinexe2x80x9d or xe2x80x9cbulk drugxe2x80x9d mean a form of amifostine which is used in preparing dosage forms, but is not suitable for parenteral administration to a patient. The term encompasses amifostine as disclosed by U.S. Pat. No. 3,892,824, including, but not limited to, mono-, di- and trihydrate forms of amifostine.
As used herein, the term xe2x80x9ccrystalline,xe2x80x9d when used to describe a component or product, means that the component or product is crystalline as determined by x-ray diffraction. See, e.g., Remington""s Pharmaceutical Sciences, 18th ed. page 173; The United States Pharmacopeia, 23rd ed. (1995) pages 1843-1844.
As used herein, the term xe2x80x9camorphousxe2x80x9d means that the component or product in question is not crystalline as determined by x-ray diffraction.
It should be recognized that a multi-component product, e.g., a product having amifostine and excipients and/or stabilizers, may have crystalline and amorphous components, e.g., amorphous amifostine and crystalline excipients and/or stabilizers.
As used herein, the terms xe2x80x9cdegradationxe2x80x9d and xe2x80x9cdecompositionxe2x80x9d when used in connection with amifostine refer to the production of 2-[(3-aminopropyl)amino]ethane thiol (WR1065) and phosphoric acid from amifostine.
As used herein, the term xe2x80x9cAmorphous Amifostine Ixe2x80x9d means a dosage form of amifostine that contained amorphous amifostine and which gave an average of about 3.5% degradation product (i.e., 2-[(3-aminopropyl)amino]ethane thiol) at about 5xc2x0 C. for 2 years. An example of the preparation of Amorphous Amifostine I is described in the Background of the Invention section above.
As used herein, the term xe2x80x9cAmorphous Amifostine IIxe2x80x9d refers to a dosage form of this invention which is suitable for reconstitution and parenteral administration to a patient. In particular, Amorphous Amifostine II refers to a dosage form of amorphous amifostine as described herein.
As used herein, the terms xe2x80x9cstabilityxe2x80x9d and xe2x80x9cthermal stabilityxe2x80x9d refer to the ability of a composition to withstand degradation or decomposition when kept at a particular temperature for a specified period of time, preferably under inert atmosphere. Appropriate means of determining stability are defined herein.
As used herein, the term xe2x80x9cthermally-stablexe2x80x9d means more stable than Amorphous Amifostine I (i.e., the previously commercial amorphous dosage form described in the Background of the Invention section above).
As used herein, the term xe2x80x9cstabilizerxe2x80x9d means a compound or mixture of compounds that when mixed in a sufficient amount with bulk amifostine, and used in the production of an amifostine dosage form, increases the thermal-stability of the dosage form, for example by reducing the amount of 2-[(3-aminopropyl)amino]ethane thiol formed by it over time.
As used herein, a range of numbers or values defined by the use of the term xe2x80x9cbetweenxe2x80x9d includes the particular numbers or values used to describe that range.
As used herein, the term xe2x80x9cmonthxe2x80x9d means a period of time of between about 26 days and about 33 days.
As used herein, the term xe2x80x9cweight percentxe2x80x9d when used to describe the amount of degradation product in a dosage form means the weight of degradation product based upon the weight of amifostine originally in that dosage form.
As known to those skilled in the art, accelerated studies can be used for the determination of stabilities and these temperatures. See, e.g., L. Lachman, et al. The Theory and Practice of Industrial Pharmacy pages 766-67 (1986). The less a compound or mixture of compounds degrades when kept at a particular temperature for a particular time, the more thermally-stable it is.
As used herein, the terms xe2x80x9crefrigerationxe2x80x9d or xe2x80x9crefrigeration conditionsxe2x80x9d mean the maintenance of a temperature of between about 1xc2x0 C. and about 8xc2x0 C.
As used herein, the terms xe2x80x9cfreezexe2x80x9d or xe2x80x9cfreezer conditionsxe2x80x9d mean the maintenance of a temperature of below about 0xc2x0 C., particularly between about 0xc2x0 C. and about xe2x88x9220xc2x0 C.
As used herein, the term xe2x80x9cparticulate-freexe2x80x9d means a solution that is sterile, suitable for bolus injection, intravenous infusion, or subcutaneous administration, and meets the particulate matter test described in U.S. Pharmacopia, page 1816 (23rd ed., 1995). Specifically, a solution is particulate-free if the average number of particles having a diameter of greater than 10 xcexcm in the solution does not exceed 6000 per container and the average number of particles having a diameter of greater than 25 xcexcm in the solution does not exceed 600 per container.